17 Coarse Dispersions Chapter Objectives At the conclusion of this chapter the student should be able to: 1. Describe what pharmaceutical suspensions are and what roles they play in the pharmaceutical sciences. 2. Discuss the desirable qualities of pharmaceutical suspensions. 3. Discuss the factors that affect the stability of suspensions and explain flocculation. 4. Describe settling and sedimentation theory and calculate sedimentation rates. 5. Define and calculate the two useful sedimentation parameters, sedimentation volume and degree of flocculation. 6. Describe the approaches commonly used in the preparation of physically stable suspensions. 7. Define pharmaceutical emulsion and emulsifying agent and identify the main types of emulsions. 8. Discuss the four classifications of pharmaceutical emulsion instability. 9. Understand semisolids, thixotropic properties, syneresis, and swelling. 10. Classify pharmaceutical semisolids. 11. Describe coarse dispersions and give examples. Particulate systems have been classified on the basis of size into molecular dispersions (Chapter 5), colloidal systems (Chapter 16), and coarse dispersions (this chapter). This chapter attempts to provide the pharmacist with an insight into the role of physics and chemistry in the research and development of the several classes of coarse dispersions. The theory and technology of these important pharmaceutical classes are based on interfacial and colloidal principles, micromeritics, and rheology (Chapters 15, 16, 18, and 19, respectively). Suspensions A pharmaceutical suspension is a coarse dispersion in which insoluble solid particles are dispersed in a liquid medium. The particles have diameters for the most part greater than 0.1 µm, and some of the particles are observed under the microscope to exhibit Brownian movement if the dispersion has a low viscosity. Examples of oral suspensions are the oral antibiotic syrups, which normally contain 125 to 500 mg per 5 mL of solid material. When formulated for use as pediatric drops, the concentration of suspended material is correspondingly greater. Antacid and radiopaque suspensions generally contain high concentrations of dispersed solids. Externally applied suspensions for topical use are legion and are designed for dermatologic, cosmetic, and protective purposes. The concentration of dispersed phase may exceed 20%. Parenteral suspensions contain from 0.5% to 30% of solid particles. Viscosity and particle size are significant factors because they affect the ease of injection and the availability of the drug in depot therapy. Key Concept Suspensions Suspensions contribute to pharmacy and medicine by supplying insoluble and what often would otherwise be distasteful substances in a form that is pleasant to the taste, by providing a suitable form for the application of dermatologic materials to the skin and sometimes to the mucous membranes, and for the parenteral administration of insoluble drugs. Therefore, pharmaceutical suspensions can be classified into three groups: orally administered mixtures, externally applied lotions, and injectable preparations. An acceptable suspension possesses certain desirable qualities, including the following. The suspended material should not settle rapidly; the particles that do settle to the bottom of the container must not form a hard cake but should be readily redispersed into a uniform mixture when the container is shaken; and the suspension must not be too viscous to pour freely from the orifice of the bottle or to flow through a syringe needle. In the case of an external lotion, the product must be fluid enough to spread easily over the affected area and yet must not be so mobile that it runs off the surface to which it is applied; the lotion must dry quickly and provide an elastic protective film that will not rub off easily; and it must have an acceptable color and odor. It is important that the characteristics of the dispersed phase be chosen with care so as to produce a suspension having optimum physical, chemical, and pharmacologic properties. Particle-size distribution, specific surface area, inhibition of crystal growth, and changes in polymorphic form are of special significance, and the formulator must ensure that these and other properties1,2,3 do not change sufficiently P.411 during storage to adversely affect the performance of the suspension. Finally, it is desirable that the product contain readily obtainable ingredients that can be incorporated into the mixture with relative ease by the use of standard methods and equipment. The remainder of this section will be devoted to a discussion of some of the properties that provide the desirable characteristics just enumerated. For pharmaceutical purposes, physical stability of suspensions may be defined as the condition in which the particles do not aggregate and in which they remain uniformly distributed throughout the dispersion. Because this ideal situation is seldom realized, it is appropriate to add that if the particles do settle, they should be easily resuspended by a moderate amount of agitation. Interfacial Properties of Suspended Particles Little is known about energy conditions at the surfaces of solids, yet knowledge of the thermodynamic requirements is needed for the successful stabilization of suspended particles. Work must be done to reduce a solid to small particles and disperse them in a continuous medium. The large surface area of the particles that results from the comminution is associated with a surface free energy that makes the system thermodynamically unstable, by which we mean that the particles are highly energetic and tend to regroup in such a way as to decrease the total area and reduce the surface free energy. The particles in a liquid suspension therefore tend to flocculate, that is, to form light, fluffy conglomerates that are held together by weak van der Waals forces. Under certain conditions—in a compacted cake, for example—the particles may adhere by stronger forces to form what are termed aggregates. Caking often occurs by the growth and fusing together of crystals in the precipitates to produce a solid aggregate. The formation of any type of agglomerate, either floccules or aggregates, is taken as a measure of the system's tendency to reach a more thermodynamically stable state. An increase in the work, W, or surface free energy, ΔG, brought about by dividing the solid into smaller particles and consequently increasing the total surface area, ΔA, is given by where γSL is the interfacial tension between the liquid medium and the solid particles. Example 17-1 Surface Free Energy Compute the change in the surface free energy of a solid in a suspension if the total surface is increased from 103 to 107 cm2. Assume that the interfacial tension between the solid and the liquid medium, γSL, is 100 dynes/cm. The initial free energy is When the surface area is 107 cm2, 9 5 9 2 The change in the free energy, ΔG21, is 10 - 10 [congruent] 10 erg/cm . The free energy has been increased by 109, which makes the system more thermodynamically unstable. To approach a stable state, the system tends to reduce the surface free energy; equilibrium is reached when ΔG = 0. This condition can be accomplished, as seen from equation (17-1), by a reduction of interfacial tension, or it can be approached by a decrease of the interfacial area. The latter possibility, leading to flocculation or aggregation, can be desirable or undesirable in a pharmaceutical suspension, as considered in a later section. The interfacial tension can be reduced by the addition of a surfactant but cannot ordinarily be made equal to zero. A suspension of insoluble particles, then, usually possesses a finite positive interfacial tension, and the particles tend to flocculate. An analysis paralleling this one could also be made for the breaking of an emulsion. The forces at the surface of a particle affect the degree of flocculation and agglomeration in a suspension. Forces of attraction are of the London–van der Waals type; the repulsive forces arise from the interaction of the electric double layers surrounding each particle. The formation of the electric double layer is considered in detail inChapter 15, which deals with interfacial phenomena. The student is advised to review, at this point, the section dealing with the electrical properties of interfaces because particle charge, electric double-layer formation, and zeta potential are all relevant to the present topic. The potential energy of two particles is plotted in Figure 17-1 as a function of the distance of separation. Shown are the curves depicting the energy of attraction, the energy of repulsion, and the net energy, which has a peak and two minima. When the repulsion energy is high, the potential barrier is also high, and collision of the particles is opposed. The system remains deflocculated, and, when sedimentation is complete, the particles form a close-packed arrangement with the smaller particles filling the voids between the larger ones. Those particles lowest in the sediment are gradually pressed together by the weight of the ones above; the energy barrier is thus overcome, allowing the particles to come into close contact with each other. To resuspend and redisperse these particles, it is again necessary to overcome the high-energy barrier. Because this is not easily achieved by agitation, the particles tend to remain strongly attracted to each other and form a hard cake. When the particles are flocculated, the energy barrier is still too large to be surmounted, and so the approaching particle resides in the second energy minimum, which is at a distance of separation of perhaps 1000 to 2000 Å. This distance is sufficient to form the loosely structural flocs. These concepts evolve from the Derjaguin and Landau, Verwey and Overbeek (DLVO) theory for the stability of lyophobic sols. Schneider et al.4 prepared a computer program for P.412 calculating the repulsion and attraction energies in pharmaceutical suspensions. They showed the methods of handling the DLVO equations and the careful consideration that must be given to the many physical units involved.